WO1997006824A2 - Bioconjugates of manganese complexes and their application as catalysts - Google Patents

Bioconjugates of manganese complexes and their application as catalysts Download PDF

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Publication number
WO1997006824A2
WO1997006824A2 PCT/US1996/012767 US9612767W WO9706824A2 WO 1997006824 A2 WO1997006824 A2 WO 1997006824A2 US 9612767 W US9612767 W US 9612767W WO 9706824 A2 WO9706824 A2 WO 9706824A2
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Prior art keywords
alkyl
aryl
groups
attached
acid
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PCT/US1996/012767
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English (en)
French (fr)
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WO1997006824A3 (en
Inventor
William L. Neumann
Dennis P. Riley
Randy H. Weiss
Susan L. Henke
Patrick J. Lennon
Karl W. Aston
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Monsanto Company
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Priority to PL96324993A priority Critical patent/PL324993A1/xx
Priority to JP09509336A priority patent/JP2000513322A/ja
Priority to BR9610347A priority patent/BR9610347A/pt
Priority to AU67655/96A priority patent/AU700958B2/en
Priority to IL12304096A priority patent/IL123040A0/xx
Priority to EP96928057A priority patent/EP0844886A2/en
Publication of WO1997006824A2 publication Critical patent/WO1997006824A2/en
Priority to BR9708179A priority patent/BR9708179A/pt
Priority to CA002249011A priority patent/CA2249011A1/en
Priority to CN97194351A priority patent/CN1225631A/zh
Priority to EP97907685A priority patent/EP0891338A1/en
Priority to AU19624/97A priority patent/AU1962497A/en
Priority to CZ982711A priority patent/CZ271198A3/cs
Priority to JP9532611A priority patent/JP2000508625A/ja
Priority to IL12588997A priority patent/IL125889A0/xx
Priority to PCT/US1997/002566 priority patent/WO1997033877A1/en
Publication of WO1997006824A3 publication Critical patent/WO1997006824A3/en
Priority to NO980649A priority patent/NO980649L/no
Priority to MXPA/A/1998/001322A priority patent/MXPA98001322A/xx
Priority to NO984164A priority patent/NO984164L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This present invention relates to compounds effective as catalysts for dismutating superoxide.
  • This invention relates to manganese (II) or manganese (III) complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalytically dismutate superoxide.
  • this invention relates to manganese complexes of nitrogen-containing fifteen-membered macrocyclic ligands which are conjugated to a targeting biomolecule.
  • the enzyme superoxide dismutase catalyzes the conversion of superoxide into oxygen and hydrogen peroxide according to equation (1) (hereinafter referred to as dismutation).
  • Reactive oxygen metabolites derived from superoxide are postulated to contribute to the tissue pathology in a number of
  • O 2 - + O 2 - + 2H+ ⁇ O 2 + H 2 O 2 (1) inflammatory diseases and disorders, such as reperfusion injury to the ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis,
  • Atherosclerosis hypertension, metastasis, psoriasis, organ transplant rejections, radiation-induced injury, asthma, influenza, stroke, burns and trauma.
  • Reactive oxygen metabolites and reperfusion injury aberrant triggering of
  • the manganese complexes of nitrogen-containing fifteen-membered macrocyclic ligands that are low molecular weight mimics of superoxide dismutase (SOD) are useful as therapeutic agents and avoid many of the problems associated with SOD enzymes.
  • SOD superoxide dismutase
  • increased dosages are sometimes necessary in order to obtain an efficacious concentration at the site of interest. Such increased dosages can sometimes result in undesirable side effects in the patient.
  • the macrocycles or manganese complexes of the present invention can be attached, i.e. conjugated, to one or more targeting biomolecule(s) via a linker group to form a targeting biomolecule-macrocycle or targeting biomolecule-manganese complex conjugate.
  • nitrogen-containing fifteen-membered macrocyclic ligands that can be targeted to a specific site in the body.
  • bioconjugates of manganese (II) or manganese (III) complexes of nitrogen-containing fifteen-membered macrocyclic ligands wherein (l) one to five of the "R” groups are attached to biomolecules via a linker group, (2) one of X, Y and Z is attached to a biomolecule via a linker group, or (3) one to five of the "R" -groups and one of X, Y and Z are attached to biomolecules via a linker group; and biomolecules are independently selected from the group consisting of steroids, carbohydrates, fatty acids, amino acids, peptides, proteins, antibodies, vitamins, lipids, phospholipids, phosphates,
  • phosphonates, nucleic acids, enzyme substrates, enzyme inhibitors and enzyme receptor substrates and the linker group is derived from a substituent attached to the "R" group or X, Y and Z which is reactive with the
  • biomolecule is selected from the group consisting of -NH 2 , -NHR 10 , -SH, -OH, -COOH, -COOR 10 , -CONH 2 , -NCO, -NCS, -COOX", alkenyl, alkynyl, halide, tosylate, mesylate, tresylate, triflate and phenol, wherein R 10 is alkyl, aryl, or alkylaryl and X" is a halide.
  • the present invention is directed to
  • R, R', R 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 6 ', R 7 , R 7 ', R 8 , R 8 ', R 9 and R 9 ' independently
  • cycloalkyl cycloalkenyl, cycloalkylalkyl,
  • alkylcycloalkyl alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the
  • heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent; and combinations thereof; and wherein (1) one to five of the "R" groups are attached to biomolecules via a linker group, (2) one of X, Y and Z is attached to a biomolecule via a linker group, or (3) one to five of the "R” groups and one of X, Y and Z are attached to biomolecules via a linker group; and biomolecules are independently selected from the group consisting of steroids, carbohydrates, fatty acids, amino acids, peptides, proteins, antibodies, vitamins, lipids, phospholipids, phosphates,
  • phosphonates, nucleic acids, enzyme substrates, enzyme inhibitors and enzyme receptor substrates and the linker group is derived from a substituent attached to the "R" group or X, Y and Z which is reactive with the
  • biomolecule is selected from the group consisting of -NH 2 , -NHR 10 , -SH, -OH, -COOH, -COOR 10 , -CONH 2 , -NCO, -NCS, -COOX", alkenyl, alkynyl, halide, tosylate, mesylate, tresylate, triflate and phenol, wherein R 10 is alkyl, aryl, or alkylaryl and X" is a halide.
  • X, Y and Z represent suitable ligands or charge-neutralizing anions which are derived from any
  • X, Y and Z are independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino,
  • alkyl sulfonic acid isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid (such as acetic acid, trifluoroacetic acid, oxalic acid), aryl carboxylic acid (such as benzoic acid, phthalic acid), urea, alkyl urea, aryl urea, alkyl aryl urea,
  • phosphine alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen
  • hexafluoroantimonate hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,
  • thiotosylate and anions of ion exchange resins, or systems where one or more of X,Y and Z are independently attached to one or more of the "R" groups, wherein n is 0 or 1.
  • the preferred ligands from which X, Y and Z are selected include halide, organic acid, nitrate and bicarbonate anions.
  • linker groups also termed herein “linker” are derived from the specified functional groups
  • the functional groups are selected from the group consisting of -NH 2 , -NHR 10 , -SH, -OH, -COOH, -COOR 10 , -CONH 2 , -NCO, -NCS, -COOX” , alkenyl, alkynyl, halide, tosylate, mesylate, tresylate, triflate and phenol wherein R 10 is alkyl, aryl, or alkaryl and X" is a halide.
  • the preferred alkenyl group is ethenyl and the preferred alkynyl group is ethynyl.
  • the functional groups on the "R" groups or X, Y and Z are reactive with the biomolecule, i.e. reactive with a functional group on the steroids, carbohydrates, fatty acids, amino acids, peptides, proteins, antibodies, vitamins, lipids, phospholipids, phosphates,
  • linker precursor may be present on the “R” groups at the time the macrocycle is prepared or it may be added or modified after preparation of the macrocycle or manganese complex thereof.
  • linker precursor can be present on an axial ligand, i.e. X, Y or Z, when the manganese complex is prepared or an exchange reaction of the axial ligands is conducted to exchange the axial ligands present in the manganese complex.
  • the macrocycle of the present invention can be complexed with manganese either before or after
  • conjugation with the targeting biomolecule depending on the specific biomolecule utilized.
  • the conjugate of the macrocyclic complex and the targeting biomolecule is defined herein as a "bioconjugate”.
  • Targeting agents are typically biomolecules.
  • the biomolecules of the invention are biologically active molecules that are site specific, i.e. known to
  • biomolecules are selected to direct the tissue distribution of the bioconjugate via receptor binding, membrane association, membrane solubility, and the like.
  • biomolecules include, for example, steroids, carbohydrates (including monosaccharides, disaccharides and polysaccharides), fatty acids, amino acids, peptides, proteins, antibodies (including polyclonal and monoclonal and fragments thereof), vitamins, lipids, phospholipids, phosphates,
  • biomolecules also include those biomolecules which are combinations of the above biomolecules, such as a combination of a steroid with a carbohydrate, e.g. digitonin.
  • biomolecules which can be utilized to target a desired organ or tissue are known in the art or it will be readily apparent to those of ordinary skill in the art.
  • biomolecules of the invention are commercially available or can readily be prepared by one of ordinary skill in the art using conventional methods.
  • a maximum of one "R" group attached to the carbon atoms located between nitrogen atoms in the macrocycle has a biomolecule attached via a linker.
  • the preferred compounds are those which have one to five, most
  • the preferred compounds are those wherein at least one, more preferably at least two, of the "R" groups, in addition to the "R" groups which are attached to a biomolecule, represent alkyl, cycloalkyl alkyl and aralkyl radicals and the remaining "R” groups not attached to a biomolecule represent hydrogen, a saturated, partially saturated or unsaturated cyclic or a nitrogen containing heterocycle.
  • R 1 or R' 1 and R 2 or R' 2 , R 3 or R' 3 and R 4 or R' 4 , R 5 or R' 5 and R 6 or R' 6 , R 7 or R' 7 and R 8 or R' 8 , and R 9 or R' 9 and R or R' together with the carbon atoms to which they are attached represent a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms and the remaining "R" groups in addition to the "R" groups which are attached to a biomolecule via a linker are hydrogen, nitrogen containing heterocycles or alkyl groups, and those wherein at least one, preferably two, of R or R' and R 1 or R' 1 , R 2 or R' 2 and R 3 or R' 3 , R 4 or R' 4 and R 5 or R' 5 , R 6 or R' 6 , and R 7 or R' 7 , and R 8 or R' 8 and R 9 or R' 9 together
  • heterocycle having 2 to 20 carbon atoms and the remaining “R” groups in addition to the "R” groups which are attached to a biomolecule via a linker are independently selected from hydrogen, saturated,
  • R groups means all of the R groups attached to the carbon atoms of the macrocycle, i.e., R, R', R 1 , R' 1 , R 2 , R' 2 , R 3 , R' 3 , R 4 , R' 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 , R' 9 , R 9 and R' 9 .
  • composition in unit dosage form useful for dismutating superoxide comprising (a) a
  • the commonly accepted mechanism of action of the manganese-based SOD enzymes involves the cycling of the manganese center between the two oxidation states
  • Mn(II) oxidation is a one-electron process; namely it is the oxidation of the Mn(II) complex to the Mn(III) complex.
  • Mn(III) oxidation state is involved in the catalytic cycle.
  • Mn(III) complexes of all these ligands are equally competent as SOD catalysts, since it does not matter which form (Mn(II) or Mn(III)) is present when superoxide is present because superoxide will simply reduce Mn(III) to Mn(II) liberating oxygen.
  • alkyl alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 22 carbon atoms, preferably from about 1 to about 18 carbon atoms, and most preferably from about 1 to about 12 carbon atoms which optionally carries one or more substituents selected from (1) -NR 30 R 31 wherein R 30 and R 31 are
  • R 30 is hydrogen, alkyl, aryl or aralkyl
  • R 31 is selected from the group consisting of -NR 32 R 33 , -OH, -OR 34 , ; wherein R 32 and R 33 are independently hydrogen, alkyl, aryl or acyl, R 34 is alkyl, aryl or alkaryl, Z is hydrogen, alkyl, aryl, alkaryl, -OR 34 , -SR 34 or -NR 40 R 41 wherein R 40 and R 41 are independently selected from hydrogen, alkyl, aryl or alkaryl, Z is alkyl, aryl, alkaryl, -OR 34 , -SR 34 or -NR 40 R 41 , R 35 is alkyl, aryl, -OR 34 , or -NR 40 R 41 , R 36 is alkyl, aryl or -NR 40 R 41 R 37 is alkyl, aryl or alka
  • R 43 is -OH , -OR 34 or -NR 32 R 33
  • a and B are independently -OR 34 , -SR 34 or -NR 32 R 33 .
  • R 44 is halide , alkyl , aryl , alkaryl , -OH , -OR 34 , -SR 34 or -NR 32 R 33 ;
  • R 45 is hydrogen , alkyl , aryl , alkaryl , -NR 32 R 33 , ;
  • D and E are independently -OR 34 or -NR 32 R 33 ; wherein R 46 is halide, -OH, -SH, -OR 34 , -SR 34 or -NR 32 R 33 ; or (6) amine oxides of the formula .
  • R 30 and R 31 are not hydrogen;
  • F and G are independently -OH, -SH, -OR 34 , -SR 34 or -NR 32 R 33 ; or
  • Alkyl, aryl and alkaryl groups on the substituents of the above-defined alkyl groups may contain one additional substituent but are preferably unsubstituted.
  • examples of such radicals include, but are not limited to, methyl, ethyl,
  • alkenyl alone or in combination, means an alkyl radical having one or more double bonds.
  • alkenyl radicals include, but are not limited to, ethenyl, propenyl, 1-butenyl, cis-2-butenyl, trans- 2-butenyl, iso-butylenyl, cis-2-pentenyl, trans-2- pentenyl, 3-methyl-1-butenyl, 2,3-dimethyl-2-butenyl, 1-pentenyl, 1-hexenyl, 1-octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, cis- and trans-9-octadecenyl, 1,3-pentadienyl, 2,4-pentadienyl,
  • alkynyl alone or in combination, means an alkyl radical having one or more triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl (propargyl), 1-butynyl, 1-octynyl, 9-octadecynyl, 1,3-pentadiynyl, 2,4-pentadiynyl, 1,3-hexadiynyl, and 2,4-hexadiynyl.
  • cycloalkyl alone or in combination means a cycloalkyl radical containing from 3 to about 10, preferably from 3 to about 8, and most preferably from 3 to about 6, carbon atoms.
  • cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl,
  • cycloalkylalkyl means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
  • examples of cycloalkylalkyl radicals include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl,
  • cycloalkylcycloalkyl means a cycloalkyl radical as defined above which is substituted by another cycloalkyl radical as defined above.
  • cycloalkylcycloalkyl radicals include, but are not limited to, cyclohexylcyclopentyl and
  • cyclohexylcyclohexyl cyclohexylcyclohexyl.
  • cycloalkenyl alone or in combination, means a cycloalkyl radical having one or more double bonds. Examples of cycloalkenyl radicals include, but are not limited to, cyclopentenyl,
  • cycloalkenylalkyl means an alkyl radical as defined above which is substituted by a cycloalkenyl radical as defined above.
  • examples of cycloalkenylalkyl radicals include, but are not limited to,
  • alkylcycloalkyl and “alkenylcycloalkyl” mean a
  • alkylcycloalkyl and alkenylcycloalkyl radicals include, but are not limited to,
  • alkylcycloalkenyl and “alkenylcycloalkenyl” means a cycloalkenyl radical as defined above which is
  • alkyl or alkenyl radical as defined above.
  • alkylcycloalkenyl alkylcycloalkenyl
  • alkenylcycloalkenyl radicals include, but are not limited to, 1-methyl-2-cyclopentenyl,
  • aryl alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more
  • aralkyl alone or in combination, means an alkyl or cycloalkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl, and the like.
  • heterocyclic means ring structures containing at least one other kind of atom, in addition to carbon, in the ring. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
  • heterocyclics include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl,
  • saturated, partially saturated or unsaturated cyclic means fused ring structures in which 2 carbons of the ring are also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 3 to 20 carbon atoms, preferably 5 to 10 carbon atoms, and can also contain one or more other kinds of atoms in addition to carbon. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
  • the ring structure can also contain more than one ring.
  • saturated, partially saturated or unsaturated ring structure means a ring structure in which one carbon of the ring is also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 3 to 20, preferably 5 to 10, carbon atoms and can also contain nitrogen, oxygen and/or sulfur atoms.
  • nitrogen containing heterocycle means ring structures in which 2 carbons and a nitrogen of the ring are also part of the fifteen- membered macrocyclic ligand.
  • the ring structure can contain 2 to 20, preferably 4 to 10, carbon atoms, can be partially or fully unsaturated or saturated and can also contain nitrogen, oxygen and/or sulfur atoms in the portion of the ring which is not also part of the fifteen-membered macrocyclic ligand.
  • organic acid anion refers to carboxylic acid anions having from about 1 to about 18 carbon atoms.
  • halide means chloride or bromide.
  • the macrocyclic ligands useful in the complexes of the present invention can be prepared according to the general procedure shown in Scheme A set forth below.
  • an amino acid amide which is the corresponding amide derivative of a naturally or non-naturally
  • amino acid amide can be the amide derivative of any one of many well known amino acids.
  • Preferred amino acid amides are those represented by the formula:
  • R is derived from the D or L forms of the amino acids Alanine, Aspartic acid, Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Proline,
  • Phenylalanine, Serine, Tryptophan, Threonine, Tyrosine, Valine and /or the R groups of unnatural ⁇ -amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether, aldehyde, amine, nitrile, halo, thiol, sulfoxide, sulfone,
  • unnatural ⁇ -amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloal
  • sulfonic acid sulfide, disulfide, phosphonic acid, phosphinic acid, phosphine oxides, sulfonamides, amides, amino acids, peptides, proteins, carbohydrates, nucleic acids, fatty acids, lipids, nitro, hydroxylamines, hydroxamic acids, thiocarbonyls, borates, boranes, boraza, silyl, siloxy, silaza, and combinations thereof.
  • R represents hydrogen, alkyl, cycloalkylalkyl, and aralkyl radicals.
  • the diamine is then tosylated to produce the di-N-tosyl derivative which is reacted with a di-O-tosylated tris-N-tosylated triazaalkane diol to produce the corresponding substituted
  • N-pentatosylpentaazacycloalkane N-pentatosylpentaazacycloalkane.
  • The- tosyl groups are then removed and the resulting compound is reacted with a manganese (II) compound under essentially anhydrous and anaerobic conditions to form the corresponding
  • the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese compound.
  • the complexes of the present invention wherein R 9 , and R 2 are alkyl, and R 3 , R' 3 , R 4 , R' 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 and R' 8 can be alkyl, arylalkyl or cycloalkylalkyl and R or R' and R 1 or R' 1 together with the carbon atoms they are attached to are bound to form a nitrogen containing heterocycle, can also be prepared according to the general procedure shown in Scheme B set forth below utilizing methods known in the art for preparing the manganese (II)
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the diacid dichloride route shown in Scheme C set forth below.
  • a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris
  • dialkylated with a suitable electrophile to produce a derivative of a dicarboxylic acid.
  • This derivative of a dicarboxylic acid is treated to produce the dicarboxylic acid, which is then treated with a suitable reagent to form the diacid dichloride.
  • the desired vicinal diamine is obtained in any of several ways.
  • One way which is useful is the preparation from an aldehyde by reaction with cyanide in the presence of ammonium chloride followed by treatment with acid to produce the alpha ammonium nitrile. The latter compound is reduced in the presence of acid and then treated with a suitable base to produce the vicinal diamine.
  • the vicinal diamines have been prepared by the route shown (known as the Strecker synthesis) and vicinal diamines were purchased when commercially available. Any method of vicinal diamine preparation could be used.
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the pyridine diamide route shown in Scheme D as set forth below.
  • a polyamine such as a tetraaza compound, containing two primary amines is condensed with dimethyl 2,6-pyridine dicarboxylate by heating in an appropriate solvent, e.g., methanol, to produce a macrocycle
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the bis(haloacetamide) route shown in Scheme E set forth below.
  • a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris
  • a bis(haloacetamide), e.g., a bis(chloroacetamide), of a vicinal diamine is prepared by reaction of the diamine with an excess of haloacetyl halide, e.g., chloroacetyl chloride, in the presence of a base.
  • haloacetyl halide e.g., chloroacetyl chloride
  • the macrocyclic ligands useful in the complexes of the present invention wherein R 1 , R ' 1 , R 2 , R ' 2 are derived from a diamino starting material and R 5 , R ' 5 , R 7 , R ' 7 and R 9 , R ' 9 can be H or any functionality previously described, can be prepared according to the pseudopeptide method shown in Scheme F set forth below.
  • R 1 , R ' 1 , R 2 and R ' 2 are the substituents on adjacent carbon atoms in the product macrocyclic ligand as set forth above, can be used in this method in combination with any amino acids.
  • the diamine can be produced by any conventional method known to those skilled in the art.
  • the R groups in the macrocycle derived from substituents on the ⁇ -carbon of ⁇ -amino acids, i.e. R 5 , R ' 5 , R 7 , R ' 7 , R 9 and R ' 9 could be derived from the D or L forms of the amino acids Alanine,
  • Aspartic acid Aspartic acid, Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine,
  • ⁇ -amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their
  • the ligands or charge-neutralizing anions, i.e. X, Y and Z are anions or ligands that cannot be introduced directly from the manganese compound, the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese compound.
  • the macrocyclic ligands useful in the complexes of the present invention wherein R 1 , R' 1 , R 3 , R' 3 , R 5 , R' 5 , R 7 , R' 7 , R 9 and R' 9 can be H or any functionality as previously described, can be prepared according to the general peptide method shown in Scheme G set forth below.
  • the R groups in the macrocycle derived from substitutents on the ⁇ -carbon of ⁇ -amino acids, i.e. R 1 , R' 1 , R 3 , R' 3 , R 5 , R' 5 , R 7 , R' 7 , R 9 and R' 9 are defined above in Scheme F.
  • the reaction sequence to prepare the linear pentapeptide can be carried out by solid-phase preparation utilizing methods known in the art.
  • the reaction sequence could be conducted from C-terminus to N-terminus and by convergent approaches such as the coupling of di- and tri-peptides as needed.
  • a Boc-protected amino acid is coupled with an amino acid ester using standard peptide coupling reagents.
  • the new Boc-dipeptide ester is then saponified to the free acid which is coupled again to another amino acid ester.
  • the resulting Boc-tri-peptide ester is again saponified and this method is continued until the Boc-protected pentapeptide free acid has been prepared.
  • the Boc protecting group is removed under standard
  • the pentaazacyclopentadecane with lithium aluminum hydride or borane.
  • the final ligand is then reacted with a manganese (II) compound under essentially anaerobic conditions to form the corresponding manganese (II) pentaazacyclopentadecane complex.
  • the ligands or charge-neutralizing anions e.g. X,Y and Z
  • the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese compound.
  • the pentaazamacrocycles of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof.
  • the optical isomers can be obtained by
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting one or more secondary amine group(s) of the compounds of the
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the
  • optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials, such as natural amino acids.
  • the compounds or complexes of the present invention are novel and can be utilized to treat
  • reperfusion injury to an ischemic organ e.g., reperfusion injury to the ischemic myocardium
  • reperfusion injury to the ischemic myocardium e.g., reperfusion injury to the ischemic myocardium
  • Atherosclerosis thrombosis, platelet aggregation, stroke, acute pancreatitis, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, adult and infantile respiratory distress, metastasis and carcinogenesis.
  • the stopped-flow kinetic analysis is suitable for screening compounds for SOD activity and catalytic activity of the compounds or complexes of the present invention for dismutating superoxide, as shown by stopped-flow analysis, correlate to treating the above disease states and disorders.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from about l to about 100 mg/kg body weight daily and more usually about 3 to 30 mg/kg.
  • Unit dosage compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy,
  • the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above.
  • the compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic
  • parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions,
  • compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds which are known to be effective against the specific disease state that one is targeting for treatment.
  • the compounds or complexes of the invention can also be utilized as MRI contrast agents.
  • a discussion of the use of contrast agents in MRI can be found in patent application Serial No. 08/397,469, which is incorporated by reference herein.
  • R is a higher alkyl group than that indicated, or where the tosyl groups are other nitrogen or oxygen protecting groups or wherein the O-tosyl is a halide.
  • Anions having a charge other than 1, e.g., carbonate, phosphate, and hydrogen phosphate, can be used instead of anions having a charge of 1, so long as they do not adversely affect-the overall
  • manganese (III) complexes will be equivalent to the subject manganese (II) complexes.
  • Boc-(R,R)-Cyc(Ts)-Gly-OH (18.1 g, 43.1 mmol) in DMF (480 mL) was added HOBt•H 2 O (7.92 g, 51.7 mmol) and EDC•HCl (9.91 g, 51.7 mmol) and the resulting mixture was allowed to stir for 20 min at RT.
  • To this solution was added GlyOEt•HCl (6.0 g, 43.1 mmol) and TEA (7.2 mL, 51.7 mmol) and the resulting mixture was allowed to stir for 16 h thereafter.
  • the DMF was evaporated and the residue was partitioned between water (250 mL) and EtOAc (400 mL).
  • the EtOAc layer was separated and washed with 1N KHSO 4 (250 mL), water (250 mL), sat. NaHCO 3 (250 mL) and brine (250 mL) and dried (Na 2 SO 4 ).
  • Water for buffer solutions was delivered from an in-house deionized water system to a Barnstead Nanopure Ultrapure Series 550 water system and then double distilled, first from alkaline potassium permanganate and then from a dilute EDTA solution.
  • a solution containing 1.0 g of potassium permanganate, 2 liters of water and additional sodium hydroxide necessary to bring the pH to 9.0 were added to a 2-liter flask fitted with a solvent distillation head. This distillation will oxidize any trace of organic compounds in the water.
  • the final distillation was carried out under nitrogen in a 2.5-liter flask containing 1500 ml of water from the first still and 1.0 ⁇ 10 6 M EDTA. This step will remove remaining trace metals from the
  • the stopped-flow spectrometer system was designed and manufactured by Kinetic Instruments Inc. (Ann Arbor, MI) and was interfaced to a MAC IICX personal computer.
  • the software for the stopped-flow analysis was provided by Kinetics Instrument Inc. and was written in
  • Aqueous solutions to be mixed with the DMSO solution of superoxide were prepared using 80 mM concentrations of the Hepes buffer, pH 8.1 (free acid + Na form).
  • One of the reservoir syringes was filled with 5 ml of the DMSO solution while the other was filled with 5 ml of the aqueous buffer solution.
  • the entire injection block, mixer, and spectrometer cell were immersed in a thermostatted circulating water bath with a temperature of 21.0 ⁇ 0.5°C.
  • a baseline average was obtained by injecting several shots of the buffer and DMSO solutions into the mixing chamber. These shots were averaged and stored as the baseline. The first shots to be collected during a series of runs were with aqueous solutions that did not contain catalyst. This assures that each series of trials were free of contamination capable of
  • suitable math program e.g., Cricket Graph
  • manganese (II) complexes were obtained from the liner plots of In absorbance at 245 nm versus time for the dismutation of superoxide by the manganese (II) complex.
  • the manganese (II) complex of the nitrogen-containing macrocyclic ligand in Example 1 is an

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Application Number Priority Date Filing Date Title
PL96324993A PL324993A1 (en) 1995-08-17 1996-08-14 Bioconjugates of macrocyclic, nitrogen containing manganese complex ligands efficiently acting as catalysts of the superoxidic dismutation reaction
JP09509336A JP2000513322A (ja) 1995-08-17 1996-08-14 スーパーオキシドをジスムテートする触媒として有効な窒素含有大環状リガンドのマンガン錯体の生体分子結合体
BR9610347A BR9610347A (pt) 1995-08-17 1996-08-14 Bioconjugados de complexos de manganés de ligantes macrocíclicos contendo nitrogénio efetivos como catalisadores para a dismutação de superóxido
AU67655/96A AU700958B2 (en) 1995-08-17 1996-08-14 Bioconjugates of manganese complexes and their application as catalysts
IL12304096A IL123040A0 (en) 1995-08-17 1996-08-14 Manganese complexes pharmaceutical compositions containg them and their use
EP96928057A EP0844886A2 (en) 1995-08-17 1996-08-14 Bioconjugates of manganese complexes and their application as catalysts
PCT/US1997/002566 WO1997033877A1 (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
CN97194351A CN1225631A (zh) 1996-03-13 1997-03-04 有歧化过氧化物催化剂效果的含氮大环配位体锰或铁配合物的生物缀合物
CA002249011A CA2249011A1 (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
BR9708179A BR9708179A (pt) 1996-03-13 1997-03-04 Bioconjugados de complexos de manganês ou ferro de ligantes macrociclicos contendo nitrogênio eficazes como catalizadores para desmutar superoxidos
EP97907685A EP0891338A1 (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
AU19624/97A AU1962497A (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
CZ982711A CZ271198A3 (cs) 1996-03-13 1997-03-04 Biokonjugáty manganu nebo komplexy železa makrocyklických ligandů obsahujících dusík, působící jako katalyzátory pro dismutaci superoxidu
JP9532611A JP2000508625A (ja) 1996-03-13 1997-03-04 スーパーオキシドをジスムテートする触媒として有効な窒素含有大環状リガンドのマンガンまたは鉄錯体の生体分子結合体
IL12588997A IL125889A0 (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
NO980649A NO980649L (no) 1995-08-17 1998-02-16 Biokonjugater av mangankoplekser og anvendelse derav som katalysatorer
MXPA/A/1998/001322A MXPA98001322A (en) 1995-08-17 1998-02-17 Bioconjugados de complejos de manganeso de ligandos macrociclicos containing nitrogen, effective as catalysts to dismute superox
NO984164A NO984164L (no) 1996-03-13 1998-09-10 Biokonjugater av mangan eller jernkomplekser bestÕende av nitrogen-inneholdende makrocykliske ligander effektive som katalysatorer for dismutering av superoksid

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US8217026B2 (en) 1999-01-25 2012-07-10 Aeolus Sciences, Inc. Substituted porphyrins
US8252595B2 (en) 2008-05-13 2012-08-28 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US8470808B2 (en) 1999-01-25 2013-06-25 Jon D. Piganelli Oxidant scavengers for treatment of type I diabetes or type II diabetes
US9187735B2 (en) 2012-06-01 2015-11-17 University Of Kansas Metal abstraction peptide with superoxide dismutase activity
US10160719B2 (en) 2001-02-28 2018-12-25 Grunenthal Gmbh Pharmaceutical salts
US11382895B2 (en) 2008-05-23 2022-07-12 National Jewish Health Methods for treating injury associated with exposure to an alkylating species

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CN111467351A (zh) * 2011-09-26 2020-07-31 加莱拉实验室有限责任公司 用于治疗疾病的方法
WO2018152353A2 (en) * 2017-02-15 2018-08-23 Galera Labs, Llc Pentaaza macrocyclic ring complexes for local intestinal delivery
CN108752383B (zh) * 2018-05-02 2020-10-30 江苏理工学院 一种具有sod活性的吡唑羧酸酯锰配合物及其制备方法

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US8470808B2 (en) 1999-01-25 2013-06-25 Jon D. Piganelli Oxidant scavengers for treatment of type I diabetes or type II diabetes
US9289434B2 (en) 1999-01-25 2016-03-22 Aeolus Sciences, Inc. Substituted porphyrins
US8217026B2 (en) 1999-01-25 2012-07-10 Aeolus Sciences, Inc. Substituted porphyrins
US8546562B2 (en) 1999-01-25 2013-10-01 James D. Crapo Substituted porphyrins
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US10160719B2 (en) 2001-02-28 2018-12-25 Grunenthal Gmbh Pharmaceutical salts
US8252595B2 (en) 2008-05-13 2012-08-28 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US9096652B2 (en) 2008-05-13 2015-08-04 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US8975082B2 (en) 2008-05-13 2015-03-10 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US8278111B2 (en) 2008-05-13 2012-10-02 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US11382895B2 (en) 2008-05-23 2022-07-12 National Jewish Health Methods for treating injury associated with exposure to an alkylating species
US9187735B2 (en) 2012-06-01 2015-11-17 University Of Kansas Metal abstraction peptide with superoxide dismutase activity

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